PROJECT SUMMARY Despite current vaccines, Streptococcus pneumoniae (pneumococcus) remains the leading cause of community-acquired pneumonia in the elderly. As this vulnerable population is projected to reach two billion worldwide by 2050, novel preventative approaches that boost resistance to pneumococcal infections are needed. Background: The Pfeifer group engineered a novel vaccine formulation, termed Liposomal Encapsulation of Polysaccharides (LEPS) designed to account for both the breadth of bacterial serotypes and the unique progression profiles that complicate treatment options for pneumococcal disease. This vaccine candidate has matched and exceeded the capabilities of Prevnar-13 in young mice, prompting the Hypothesis that vaccination of elderly mice with the LEPS particle will induce robust immune responses relative to current pneumococcal vaccine formulations. This hypothesis will be addressed through two specific Aims: 1) Test the effect of LEPS vaccination on immune responses in young versus elderly mice where anti-pneumococcal antibody levels and function will be assessed; and 2) Test the protective efficacy of LEPS vaccination against invasive pneumococcal infections in young versus elderly mice in models of primary pneumonia, systemic infection, and secondary pneumonia following influenza co-infection. Host survival, clinical disease score, organ-specific bacterial burden, and other indicators of infection severity (organ pathology) will be measured over time across vaccine and non-vaccine pneumococcal strains to assess serotype-specific protection as well as cross protection. Significance/Innovation: The LEPS formulation combines both polysaccharides and protein antigens within the same vaccine, which by itself is innovative and able to provide capsule specific immunity as well as cross protection against other serotypes and stages of disease progression. From a manufacturing standpoint, in contrast to current formulations, the LEPS construct is cost effective and easy to generate. Here, we will test for the first time the effectiveness of the LEPS vaccine within aged animal models. Potential outcomes include treatment effectiveness beyond current vaccine formulations (i.e., PPSV and PCV), in which case, we are in an ideal situation for more extensive assessment of the LEPS platform in subsequent clinical settings. Alternatively, if the current LEPS design does not provide extended protection in the elderly, with assessment provided through the Bou Ghanem group's expertise, immunological profiling and comparison will provide the insight needed to refine the LEPS vehicle for subsequent improvements in effectiveness. Under either scenario, data from the exploratory plans outlined in this R21 application will provide the foundation to advance the LEPS vehicle (in future collaborative work between the Bou Ghanem and Pfeifer groups) as a new option for pneumococcal disease in aged populations.